Zopiclone, chemically named (±)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4b]pyrazin-5-yl-4-methylpiperazine-1-carboxylate, is a non-benzodiazepine hypnotic which has the following structure: Zopiclone and some of its uses are described by U.S. Pat. Nos. 3,862,149 and 4,220,646. Uses of the optically pure (+) and (−) enantiomers of the drug (i.e., (+)-zopiclone and (−)-zopiclone) are described by U.S. Pat. No. 5,786,357 and WO 93/10788, respectively.
Zopiclone binds at or near benzodiazepine receptor complexes. Goa, K. L. and Heel, R. C. Drugs, 32:48-65 (1986). These complexes are located both within the central nervous system and peripherally (e.g., in the endocrine system), and contain macromolecular complexes which comprise benzodiazepine and GABA binding sites. Verma, A. and Snyder, S. H., Annu. Rev. Pharmacol. Toxicol. 29:307-22 (1989). Benzodiazepine receptor complexes are further associated with, and interact with, membrane channels for chloride ion transport. Upon binding to a benzodiazepine receptor complex, zopiclone is believed to allosterically modulate the activity of the complex by increasing trans-membrane conductance of chloride ions. This stabilizes neuronal membrane potentials and dampens excitatory input. See Meldrum, B. S., Brit. J. Clin. Pharm. 27(suppl. 1):3S-11S (1989); Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p. 365 (9th ed., 1996).
Although chemically unrelated to the benzodiazepines, zopiclone possesses a spectrum of activity analogous to that of the benzodiazepines. Goa, K. L. and Heel, R. C. Drugs, 32:48-65, (1986). Zopiclone and its optically pure enantiomers are reportedly useful in the treatment of diseases and conditions including, but not limited to, epilepsy, anxiety, aggressive behavior, muscle tension, behavioral disorders, depression, schizophrenia, and endocrine disorders. See, e.g., WO 93/10787. Racemic zopiclone has been used to improve sleep in adults and geriatric patients with several types of sleep disorders including situational, transient primary and secondary insomnia. See, e.g., Bruni, J. P., Pharm. Biochem. Behav. 29:831-832 (1988).
Some compounds which bind at benzodiazepine receptors can also have affinity for muscarinic receptors such as acetylcholine receptors. Julou, L., et al., Pharmacol. Biochem. Behav. 23:653-659 (1985). Consequently, administration of such compounds can result in adverse effects caused by muscarinic agonists and antagonists. Such adverse effects include, but are not limited to, drymouth, thirst, slowing and acceleration of the heart, dilated pupils, blurred vision, restlessness, fatigue, headache, hallucinations and delirium. Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p. 142 (9th ed., 1996).
The metabolism of zopiclone is rapid and complex. When administered orally to healthy humans, the racemic drug is extensively metabolized by at least three major pathways, as shown below in Scheme 1. 
Metabolic pathways include oxidation, hydrolysis, and demethylation. An oxidation pathway produces N-oxidezopiclone, a metabolite which is reportedly less active than zopiclone and reportedly accounts for 11% of an oral dose of racemic zopiclone. A hydrolysis pathway produces an alcohol which is reportedly biologically inactive. A demethylation metabolic pathway produces N-desmethylzopiclone, a metabolite which reportedly accounts for 15% of an oral dose of racemic zopiclone, and which is also reportedly inactive. Goa, K. L. and Heel, R. C. Drugs, 32:48-65, (1986). Additional metabolites are formed from each of the three pathways shown in Scheme 1.
The full pharmacological activity of zopiclone is reportedly due to the drug itself and the N-oxide metabolite (i.e., N-oxidezopiclone). Id. Unfortunately, the single-dose elimination half-lives of both of these compounds after administration of racemic zopiclone range from only about 3.5 to about 6 hours, which limits the usefulness of zopiclone in the treatment of a wide number of disorders. For example, the rapid elimination of zopiclone and N-oxidezopiclone limits their usefulness in long-term anxiolytic treatment. The single-dose elimination half-life of the reportedly inactive N-desmethyl-zopiclone metabolite (herein referred to as “N-desmethylzopiclone”) after administration of racemic zopiclone is between about 7 and about 11 hours in healthy subjects. Id.
Racemic zopiclone possesses further disadvantages, in particular, it causes adverse side effects which include, but are not limited to, the development of a bitter taste due to salivary secretion of the drug, dry mouth, heart palpitations, drowsiness, morning tiredness, headache, dizziness, impairment of psychomotor skills and related effects. A compound is thus desired for the treatment or prevention of various disorders which does not possesses disadvantages associated with racemic zopiclone.